An asymmetry in the synthesis of leading and lagging DNA strands creates the “end problem” for replication of linear genomes.1 To overcome this problem, eukaryotic chromosomes have specialized end structures, telomeres, consisting of TTAGGG repeats.2 Telomerase3,4 is a ribonucleoprotein enzyme that elongates telomeres and therefore maintains chromosomal stability in majority of cancer cells during cell doubling5. The gradual loss of DNA from the ends of telomeres during cell doubling has been implicated in the control of cellular proliferative potential in somatic cells6.
Normal cultured human cells have a limited replication potential in culture. Normal cells in culture replicate until they reach a discrete point at which population growth ceases. This is termed mortality stage 1 (M1 stage) and is caused by the shortening of a few telomeres to a size that leads to a growth arrest called cellular senescence. This stage can be bypassed by abrogation of the function of p53 and pRB human tumor suppressor genes. The cells then can continue to proliferate with further decreases in telomere length until another check point termed mortality stage 2 (M2 stage) or crisis stage. The growth arrest in the M2 stage is caused by balance between the cell proliferation and cell death rate. At this stage, when most of the telomeres are extremely short, end-to-end fusions and chromosomal breakage-fusion cause marked chromosomal abnormalities and apoptosis. Under rare circumstances, a cell can escape M2 and become immortal by stabilizing the length of its telomeres. This occurs through the activation of the enzyme telomerase or an alternative mechanism of telomere lengthening (i.e., alternative lengthening of telomeres or ALT).7,8 
Human germline9 and the majority of cancer cells3 express telomerase. Elongation of shortened telomeres by telomerase is a major mechanism of telomere maintenance in the human cancer cells.10 Inhibition of telomerase limits the growth of human telomerase positive cancer cells11 by decreasing telomere length.
The use of nucleoside analogs (e.g., AZT) has been attempted to interfere with human telomerase activity with an aim to treat cancers. The methods disclosed in the prior art administering nucleoside analogs to modify telomerase activity, however, are not satisfactory or are not suitable in a clinical setting because their clinical utility is limited by a low therapeutic ratio, i.e., the ratio of toxic dose to effective dose.
Further, because proliferative ability of cells including cancer cells is due to the activation of telomerase mediated telomere lengthening mechanism and/or ALT mechanism, the ideal nucleoside analogs for controlling cell proliferation would be those that are effective against both the mechanisms with minimal or no toxicity against normal cells and tissues. Thus, there is need for the identification of therapeutic nucleoside analogs that can inhibit proliferating cells such as cancer cells maintaining their telomeres either by telomerase and/or ALT mechanism.